Both antibody and cellular immune responses to myoglobin were found to be under the control of 2 genes mapping in distinct subregions of the immune-response (Ir) gene region of the major histocompatibility complex (H-2) of mice. Each gene controlled the response to different determinants on the same antigen molecule - the first example of this phenomenon observed. Moreover, the gene controlling production of antibodies to a region of myoglobin also controlled T-cell proliferation to the same region, suggesting a common control mechanism. Kupffer cells (liver macrophages) were found to reconstitute the ability of macrophage-depleted T-cells to respond to antigen. When (high-responder x low-responder) F1 hybrid T-cells were used with Kupffer cells from recombinant mice bearing only one or the other myoglobin Ir gene, or both or neither, Ir gene control was found to depend on genes of the Kupffer cell. The Kupffer cells thereby selected which determinants could elicit an immune response. Thus, determinant-specific Ir genes are expressed in T-lymphocyte-macrophage interaction, but not T-cells alone. Monoclonal antimyoglobin antibodies were raised in spleen cell-plasmacytoma hybrid clones and found to be of high affinity (10 to the ninth power M to the minus first power), useful for raising anti-idiotypic antibodies.